Faculty Bibliography

Cell penetration after recognition of the SARS-CoV-2 virus by the ACE2 receptor, and the fusion of its viral envelope membrane with cellular membranes, are the early steps of infectivity. A region of the Spike protein (S) of the virus, identified as the "fusion peptide" (FP), is liberated at its N-terminal site by a specific cleavage occurring in concert with the interaction of the receptor binding domain of the Spike. Studies have shown that penetration is enhanced by the required binding of Ca2+ ions to the FPs of corona viruses, but the mechanisms of membrane insertion and destabilization remain unclear. We have predicted the preferred positions of Ca2+ binding to the SARS-CoV-2-FP, the role of Ca2+ ions in mediating peptide-membrane interactions, the preferred mode of insertion of the Ca2+-bound SARS-CoV-2-FP and consequent effects on the lipid bilayer from extensive atomistic molecular dynamics (MD) simulations and trajectory analyses. In a systematic sampling of the interactions of the Ca2+-bound peptide models with lipid membranes SARS-CoV-2-FP penetrated the bilayer and disrupted its organization only in two modes involving different structural domains. In one, the hydrophobic residues F833/I834 from the middle region of the peptide are inserted. In the other, more prevalent mode, the penetration involves residues L822/F823 from the LLF motif which is conserved in CoV-2-like viruses, and is achieved by the binding of Ca2+ ions to the D830/D839 and E819/D820 residue pairs. FP penetration is shown to modify the molecular organization in specific areas of the bilayer, and the extent of membrane binding of the SARS-CoV-2 FP is significantly reduced in the absence of Ca2+ ions. These findings provide novel mechanistic insights regarding the role of Ca2+ in mediating SARS-CoV-2 fusion and provide a detailed structural platform to aid the ongoing efforts in rational design of compounds to inhibit SARS-CoV-2 cell entry.
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Introduction. Pain is an important nonmotor symptom of Parkinson's disease (PD). Brain areas such as the hippocampus and the prefrontal cortex play an important role in the processing of pain. Since these brain areas are also involved in cognitive functioning, for example, episodic memory and executive functions, respectively, we examined whether a relationship exists between cognitive functioning and spontaneous pain in PD. Methods. Forty-eight patients with PD and 57 controls participated. Cognitive functioning was measured by a comprehensive battery of neuropsychological tests. Both the sensory-discriminative aspect and the motivational-affective aspect of pain were assessed. Multiple linear regression analyses were performed to assess a relation between cognition and pain. Results. Cognition was related to neither the sensory nor the affective aspect of pain in our sample of PD patients. Variance in pain measures was primarily explained by symptoms of depression and anxiety. Discussion. The difference between the affective and the sensory aspect of pain might be due to the neuropathology of PD, which is mainly present in areas processing the affective aspect of pain. Pain treatment might improve when mood is taken into account. We provide several explanations for the lack of an association between pain and cognition.

Traditionally, multiple sclerosis (MS) is considered to be a disease primarily affecting the white matter (WM). However, the development of some clinical symptoms such as cognitive impairment cannot be fully explained by the severity of WM pathology alone. During the past decades it became clear that gray matter (GM) damage of the brain is also of major importance in patients with MS. Thanks to improved magnetic resonance imaging techniques, the in vivo detection of GM pathology became possible, enabling a better understanding of the manifestation of various clinical symptoms, such as cognitive impairment. Using higher field strengths and specific sequences, detection of cortical lesions was increased. However, despite these improvements, visualization of cortical MS lesions remains difficult (only about 30-50% of histopathologically confirmed lesions can be detected at 7 Tesla magnetic resonance imaging (MRI)). Furthermore, more research is needed to understand the exact interplay of cortical lesions, GM atrophy and WM pathology in the development of clinical symptoms. In this review, we summarize the historical background that preceded current research and provide an overview of the current knowledge on clinical consequences of GM pathology in MS in terms of disability, cognitive impairment and other clinically important signs such as epileptic seizures.

BACKGROUND: Few studies have focused on the quality of care with regard to long-term secondary prevention after transient ischemic attack (TIA) or ischemic stroke. The aim of this study was 2-fold: (1) to determine if ischemic stroke and TIA patients are motivated for a long-term secondary prevention program after hospital discharge and (2) to study the effect of this program on the attainment of guideline-recommended secondary prevention targets. METHODS: A single-center, cohort study of ischemic stroke and TIA patients. The number of visits to the long-term secondary prevention program and the number of patients whom achieved the composite end point of optimal medical therapy at their last visit to our outpatient clinic were assessed. RESULTS: Of the 237 included ischemic stroke and TIA patients, only 164 (69%) visited the long-term secondary prevention program at least once. Of these patients, 37% reached the primary end point of optimal medical treatment at their last visit to our outpatient clinic. We found a significant increase in secondary prevention target attainment for the primary outcome of optimal medical treatment and its individual components. CONCLUSIONS: Despite our systematic approach to care for patients after ischemic stroke or TIA, we observed that 31% of our patients did not visit our outpatient clinic for the long-term secondary prevention program at all. In addition, the long-term secondary prevention program alone, consisting of regular follow-up visits and a medication treatment algorithm, was not sufficient to reach guideline-recommended treatment targets in most of our ischemic stroke and TIA patients.

BACKGROUND: Stroke guidelines emphasize the importance of adequate vascular risk factor assessment and management in transient ischemic attack (TIA) and ischemic stroke patients, but it is not clear how these guidelines are applied in routine clinical practice. The limited data that are available indicate that TIA and ischemic stroke patients often do not receive the recommended interventions. The aim of this study was to investigate practice variations in long-term secondary stroke prevention in The Netherlands. METHODS: Between June and December 2013, an invitation for a web-based survey was sent to 90 Dutch neurologists with a special interest in stroke neurology. This web-based survey contained questions regarding the organization of outpatient care for TIA and ischemic stroke patients after initial hospital assessment, pharmacologic treatment, and nonpharmacologic strategies for long-term secondary prevention. RESULTS: In total, 84 (93%) neurologists completed the survey. Although nearly all respondents reported that they follow-up TIA and ischemic stroke patients after initial hospital assessment, the number of follow-up visits and the follow-up duration were variable. A similar variation was found in treatment targets levels for both blood pressure and low-density lipoprotein cholesterol. Regarding nonpharmacologic strategies for long-term secondary stroke prevention, most respondents inform their TIA and ischemic stroke patients about the importance of smoking cessation. There is considerably less attention for the other lifestyle risk factors. CONCLUSIONS: We found considerable practice variation in long-term secondary stroke prevention. These variations may have an impact on the risk for stroke recurrence and cardiovascular disease in general.

BACKGROUND: Providing intravenous thrombolysis with short door-to-needle time is the result of a complex process that requires specific work standards. To expedite care for acute ischemic stroke patients, close collaboration between all participating health care professionals is required. The aim of this project was to reduce in-hospital treatment delay for acute ischemic stroke patients through the introduction of a standard operating procedure and by creating higher and sustained awareness of the importance of intravenous thrombolysis. METHODS: This study was set up as a before-versus-after study, divided into a preintervention period, an immediate postintervention period, and a late postintervention period. During the study, a standard operating procedure was implemented that defined the targeted standard of care to be provided to all acute stroke patients. Involved health care professionals received regular feedback to create greater awareness of the importance of this time-driven protocol. RESULTS: The median door-to-needle time decreased significantly, from 60 minutes in the preintervention period to 30 minutes in the immediate postintervention period (P < .001), and compared with the immediate postintervention period it decreased significantly further, to 25 minutes, in the late postintervention period (P < .001). The proportion of patients with a door-to-needle time <30 minutes and <20 minutes increased significantly across the 3 study periods (P < .001). CONCLUSIONS: The door-to-needle time for acute ischemic stroke patients can be reduced through the introduction of a standard operating procedure and by creating higher and sustained awareness of the importance of intravenous thrombolysis among health care professionals involved.

PURPOSE: The aim of this prospectively conducted study was to compare the diagnostic accuracy of onset versus peak latency measurements of sensory nerve action potentials in electrodiagnostic studies in diagnosing carpal tunnel syndrome. METHODS: In 156 consecutive patients with clinically defined carpal tunnel syndrome, standardized nerve conduction studies (DIG1, DIG4, PALM3) were performed. Both onset and peak latency were measured. Sensitivity was calculated using the clinical diagnosis as golden standard. Bland-Altman plots were constructed to assess the agreement for quantitative measurements. Overall agreement, positive and negative percent agreement, and Kappa coefficient were computed. RESULTS: The Bland-Altman plots, positive and negative percent agreement show good overall agreement. The kappa coefficient was 0.850, 0.847, and 0.815 for DIG1, DIG4, and PALM3, respectively. CONCLUSIONS: Onset and peak latencies used in electrodiagnostic tests show a good overall agreement in confirming the clinical diagnosis of carpal tunnel syndrome. Because onset latency measurement represents nerve conduction velocity of the fastest conducting fibers, the use of onset latencies is recommend. In case of uncontrollable stimulus artifacts, peak latencies may be used instead.